Are You Confident of the Diagnosis?

Elastosis perforans serpiginosa (EPS) represents a distinct entity within the spectrum of perforating dermatoses. It is a rare disorder characterized by transepidermal elimination of altered elastic fibers. About one-quarter of cases are associated with an underlying disorder, typically of connective tissue, or with D-penicillamine use. These include Marfan syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum (PXE), Ehlers-Danlos syndrome (type IV), Down syndrome, cutis laxa, Rothmund-Thomson syndrome, acrogeria, morphea, D-Penicillamine therapy, and scleroderma. A useful pnemonic to help remember these associations is "MOPED CRAMPS" (listed above in the order of the pnemonic). The remaining cases are idiopathic.

What you should be alert for in the history

Important questions on history include the use of D-penicillamine, as well as a thorough review of systems to assess for the possibility of associated systemic diseases.

A positive history of vision loss, cerebrovascular disease, myocardial infarction, or renovascular hypertension will point toward the possibility of pseudoxanthoma elasticum. The associated physical findings may include 2-5 mm yellow-orange papules (plucked chicken skin) and angioid streaks on the retina.

Osteogenesis imperfecta patients may have a history of fractures, hearing loss and dental caries. Physical findings include short stature, basilar skull deformities, blue sclera, scoliosis and joint laxity.

Acrogeria lacks systemic symptoms, but will have features of premature aging, with skin/subcutaneous atrophy that tends to favor the distal extremities.

Patients with Rothmund-Thomson syndrome may have a positive history of photosensitivity, osteosarcoma or cataracts. On physical examination they will typically display photodistributed poikilodermatous skin changes along with short stature, skeletal anomalies and sparse hair.

A history of focal trauma or surgery preceeding the onset of lesions had also been noted as a triggering factor.

There are currently no well-established protocols for the investigation of possible associated disorders in patients who present with EPS. A survey of 31 pediatric dermatologists found that most limit their evaluation of such patients to a thorough history and physical examination, which appears to be sufficient in otherwise healthy patients.

Characteristic findings on physical examination

The primary lesion of EPS is a slightly erythematous or skin-colored, 2-5 mm keratotic papule with a central plug or crust. If the plug is forcibly removed, bleeding from the papillary dermal blood vessels may result and the lesions may heal with superficial scarring. The papules are characteristically arranged in a serpiginous, arcuate or annular configuration and most often occur on the posterolateral aspect of the neck.

Other sites of involvement include the face, upper extremities (antecubital fossae) , lower extremities (popliteal fossae) and, less commonly, the trunk. Involvement of the penis has also been reported. Disseminated presentations of EPS, although rare, have been described. Lesions are usually symmetrically distributed, except when associated with Down syndrome or penicillamine therapy.

The lesions are usually asymptomatic; however some patients may complain of mild pruritus.

Expected results of diagnostic studies

Specific investigations include skin biopsy with Masson trichrome and Verhoeff-van Gieson stains and potassium hydroxide examination to rule out the possibility of fungal infection. Although biopsy is the gold standard used to diagnose EPS, Feldman et al. (JAAD, 1989 Jun; 20 (6): 1137- 8) suggest performing a skin scraping with a Sedi stain as a fast, inexpensive, and noninvasive method of diagnosing EPS. Elastin fibers are usually abundant in the extruded material and stain a bright red color. (Sedi stain is traditionally used for evaluation of urine sediment and can be a valuable alternative for a fast diagnosis of EPS.)

Clinically, EPS may simulate a number of annular or serpiginous eruptions such as granuloma annulare, annular sarcoidosis, dermatophytosis, porokeratosis of Mibelli, perforating pseudoxanthoma elasticum and actinic granuloma (annular elastolytic giant cell granuloma). These can be differentiated on biopsy.

The most prominent ifinding is the presence of bulky red elastic fibers and the presence of narrow transepidermal or perifollicular channels perforating through acanthotic epidermis. These could be straight or tortuous and are unrelated to follicular or sebaceous skin appendageal structures. Staining with Verhoeff-van Gieson stain reveals a local increase in elastin content, staining collagen fibers red and elastic fibers black. Light and electron microscopy of penicillamine-induced EPS demonstrates characteristic "lumpy-bumpy" or "bramble-bush" appearance of elastic fibers in both lesional and nonlesional skin, which distinguishes it from other types of EPS.

Abnormalities of collagen have also been described in patients with EPS. A chronic inflammatory infiltrate composed of lymphocytes, macrophages and multinucleated giant cells is often seen in older lesions of EPS, at the site of perforation.

Diagnosis confirmation

The histopathologic differential diagnosis of EPS includes other disorders of transepidermal elimination which may show similar features. The main clinical differential diagnostic possibilities, such as granuloma annulare, calcinosis cutis, annular sarcoidosis, tinea corporis and porokeratosis of Mibelli all have distinct histopathologic findings and can be readily differentiated from EPS.

Transepidermal elimination has also been described in PXE; however, the mineralization of elastic fibers seen in PXE is lacking in EPS.

Thus, inquiry into a history of aneurysms, poor wound healing, joint dislocation, and heart disease will help determine the possibility of associated Ehlers-Danlos or Marfan syndromes. Physical signs of the above disorders would include blue sclera, joint hypermobility/hyperextensibilty, skin hyperelasticity as well as a heart murmur.

Who is at Risk for Developing this Disease?

EPS is a disease of children and young adults. Up to 90% of cases reported in the literature involve individuals who are 30 years old or younger; however, the age range is between 3 and 89 years. EPS is a panethnic disorder, reported from almost every continent. 75% of affected persons are male, and cases associated with osteogenesis imperfecta are seen primarily in teenage boys.

The majority of cases occur sporadically in otherwise healthy individuals, but about a quarter are associated with numerous inherited disorders detailed in the introductory part of this review. These include Marfan syndrome, osteogenesis imperfecta, cutis laxa, acrogeria, Ehlers-Danlos syndrome, Rothmund-Thomson syndroma and Down syndrome. Association with renal disease is rare.

Although EPS most often occurs sporadically, rare familial cases have been described.

The natural history of the disease is that it follows an unpredictable course. In some cases the lesions heal leaving superficial scars. However, the eruption tends to persist longer, often for five to ten years before spontaneous resolution. Recurrences are common. Elastosis perforans serpiginosa (EPS) represents a distinct entity within the spectrum of perforating dermatoses. It is a rare disorder characterized by transepidermal elimination of altered elastic fibers. About one-quarter of cases are associated with an underlying disorder, typically of connective tissue, or with D-penicillamine use. These include Marfan syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum (PXE), Ehlers-Danlos syndrome (type IV), Down syndrome, cutis laxa, Rothmund-Thomson syndrome, acrogeria, morphea, D-Penicillamine therapy, and scleroderma. A useful pnemonic to help remember these associations is "MOPED CRAMPS" (listed above in the order of the pnemonic). The remaining cases are idiopathic.

What is the Cause of the Disease?

Etiology

Pathogenesis

The pathogenesis of EPS is not well established. D-penicillamine therapy for Wilson's disease, cystinuria, and rheumatoid arthritis has been strongly associated with iatrogenic form of EPS. Although the exact mechanism is unknown, it is speculated that this copper-chelating agent inhibits lysyl oxidase, a copper-dependent enzyme that deaminates lysine to form crosslinks in both collagen and elastic fibers.

Mechanical trauma and focal irritation are also thought to induce formation of epidermal and follicular channels to extrude the abnormal elastin. However, attempts to identify specific genetic or biochemical abnormalities of elastic fibers have been unsuccessful.

Systemic Implications and Complications

Although a significant proportion of EPS cases are associated with a variety of connective tissue disorders discussed in other sections, an exhaustive search for all possible systemic associations is not warranted given that the majority of patients with EPS do not have associated comorbidities. Subjecting a patient diagnosed with EPS to extensive diagnostic testing may place an undue burden on the patient in addition to having an unacceptable cost-benefit ratio for the health care system.

Treatment Options

Treatment options are listed in Table I. A consistently effective treatment for EPS is not currently available. There are no well-designed, randomized, controlled studies to support or refute any of the published treatment modalities. Rather, the existing evidence comes from anecdotal reports or small case series. In addition, treatment outcomes are difficult to evaluate as spontaneous resolution has been reported.

Table I.

Treatment options for elastosis perforans serpiginosa

Medical Treatment

Surgical Procedures

Physical Modalities

Topical corticosteroids with or without occlusion

Electrodessication and curettage

Cellophane (Scotch) tape stripping

Calcipotriene ointment 0.005%

Cryotherapy

Tretinoin 0.1%

UVB phototherapy

Tazarotene 0.1%

Laser treatments (CO2, Er:YAG, pulsed dye, flashlamp)

Glycolic acid 10-20%

Salicylic acid 5%

Imiquimod 5%

5-fluorouracil 1%

0.5% Phenol with 10% glycerine in sorbolene

Systemic isotretinoin, 40-60 mg od

Systemic corticosteroids 0.5-1 mg/kg

Numerous treatment methods have been reported, all largely ineffective in the long-term. Topical modalities include corticosteroids, calcipotriene ointment, tretinoin, tazarotene, glycolic and salicylic acid, imiquimod and 5-fluorouracil. Physical methods include cellophane (Scotch) tape stripping, electrodessication and curettage, cryotherapy, narrowband or broadband ultraviolet B (UVB) phototherapy, as well as a variety of laser treatments, including flashlamp, pulsed-dye, erbium:yttrium-aluminum-garnet and carbon dioxide, all with inconsistent efficacy. Systemic isotretinoin and corticosteroids have also been tried and produced only limited improvement.

Aggressive treatment modalities may result in scarring and postinflammatory dyspigmentation and may not be warranted, particularly if the patient is asymptomatic and does not have significant aesthetic concerns.

Optimal Therapeutic Approach for this Disease

The inherited forms of EPS tend to be generally localized and only mildly symptomatic. Thus, local measures may be successful. Topical application of retinoids, tretinoin 0.1% cream or tazarotene 0.1% gel, for 3 months can be tried first. For limited disease, cryotherapy can be efficacious. A case report described successful treatment of EPS with six 10-second courses of cryotherapy with complete resolution of the lesions. For symptomatic disease UVB phototherapy sessions, three times a week for 6 weeks need to be carried out before therapy could be deemed ineffective. Second-line options are laser treatments (listed in the table) and cellophane tape stripping. Aggressive treatment may lead to scarring and should be avoided.

Patient Management

An important aspect of management is patient education and referral to appropriate specialists for further work-up and management in cases of associated connective tissue disorders. In particular, cardiac echocardiography and an ophthalmological examination are advocated as first-line screening tests by many pediatricians in cases where clinical suspicion of an underlying connective tissue disorder exists.

Explain the natural history of EPS. It may improve spontaneously although the time course can be protracted. A multitude of treatments exist but none are uniformly effective and many treatments may need to be tried.

Unusual Clinical Scenarios to Consider in Patient Management

Cases of spontaneous resolution of EPS have been reported. However, the lesions of EPS have been reported to persist or even progress in some patients up to 10 years after discontinuation of D-penicillamine therapy.

(A report of a case of EPS treated successfully with liquid nitrogen cryotherapy: treatment was well tolerated and had minimal side effects. A comprehensive review of the published treatment modalities for EPS.)

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